rs75568433

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_182914.3(SYNE2):c.14197C>A(p.Pro4733Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,614,150 control chromosomes in the GnomAD database, including 227 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 8 hom., cov: 32)

Exomes 𝑓: 0.015 ( 219 hom. )

Consequence

SYNE2
NM_182914.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.78

Variant links:

Genes affected

SYNE2 (HGNC:17084): (spectrin repeat containing nuclear envelope protein 2) The protein encoded by this gene is a nuclear outer membrane protein that binds cytoplasmic F-actin. This binding tethers the nucleus to the cytoskeleton and aids in the maintenance of the structural integrity of the nucleus. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

SYNE2 links:

SYNE2 (HGNC:):

SYNE2 links:

ESR2 (HGNC:3468): (estrogen receptor 2) This gene encodes a member of the family of estrogen receptors and superfamily of nuclear receptor transcription factors. The gene product contains an N-terminal DNA binding domain and C-terminal ligand binding domain and is localized to the nucleus, cytoplasm, and mitochondria. Upon binding to 17beta-estradiol or related ligands, the encoded protein forms homo- or hetero-dimers that interact with specific DNA sequences to activate transcription. Some isoforms dominantly inhibit the activity of other estrogen receptor family members. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been fully characterized. [provided by RefSeq, Jul 2008]

ESR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005111128).

BP6

Variant 14-64130105-C-A is Benign according to our data. Variant chr14-64130105-C-A is described in ClinVar as [Benign]. Clinvar id is 313597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64130105-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0102 (1552/152306) while in subpopulation NFE AF= 0.0172 (1168/68024). AF 95% confidence interval is 0.0164. There are 8 homozygotes in gnomad4. There are 699 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1552 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3 linkuse as main transcript	c.14197C>A	p.Pro4733Thr	missense_variant	76/116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6 linkuse as main transcript	c.14197C>A	p.Pro4733Thr	missense_variant	76/116	1	NM_182914.3	ENSP00000450831.2		Q8WXH0-2A0A0C4DGK3

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1555

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00314

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.00739

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.00330

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0172

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.00975

AC:

2446

AN:

250990

Hom.:

AF XY:

0.00945

AC XY:

1282

AN XY:

135640

show subpopulations

Gnomad AFR exome

AF:

0.00265

Gnomad AMR exome

AF:

0.00581

Gnomad ASJ exome

AF:

0.0180

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00219

Gnomad FIN exome

AF:

0.00407

Gnomad NFE exome

AF:

0.0158

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.0154

AC:

22445

AN:

1461844

Hom.:

219

Cov.:

AF XY:

0.0150

AC XY:

10907

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00242

Gnomad4 AMR exome

AF:

0.00624

Gnomad4 ASJ exome

AF:

0.0164

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00211

Gnomad4 FIN exome

AF:

0.00446

Gnomad4 NFE exome

AF:

0.0184

Gnomad4 OTH exome

AF:

0.0133

GnomAD4 genome

AF:

0.0102

AC:

1552

AN:

152306

Hom.:

Cov.:

AF XY:

0.00939

AC XY:

699

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00308

Gnomad4 AMR

AF:

0.00738

Gnomad4 ASJ

AF:

0.0167

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.00330

Gnomad4 NFE

AF:

0.0172

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0154

Hom.:

Bravo

AF:

0.0106

TwinsUK

AF:

0.0170

AC:

ALSPAC

AF:

0.0215

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.0198

AC:

170

ExAC

AF:

0.00966

AC:

1173

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0141

EpiControl

AF:

0.0167

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 15, 2020

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Benign

0.73

DEOGEN2

Benign

0.029

.;T;T;T;T

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.92

D;D;D;D;D

MetaRNN

Benign

0.0051

T;T;T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Uncertain

2.1

M;.;M;.;.

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.7

D;.;D;D;D

REVEL

Benign

0.15

Sift

Benign

0.11

T;.;T;T;T

Sift4G

Uncertain

0.0050

D;D;D;D;D

Polyphen

1.0

D;.;D;.;.

Vest4

0.61

MVP

0.51

MPC

0.34

ClinPred

0.022

GERP RS

5.8

Varity_R

0.14

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over